To date, oral delivery of pharmaceutical and/or probiotic active ingredients has been achieved chiefly through either oral solid dosage forms or refrigerated liquid dosage forms. For oral solid dosage forms, such as a tablet or capsule, the active ingredient is commonly formulated into a powder mixture or granulation, which is then usually compressed into a tablet or encapsulated into a hard-shell capsule. For refrigerated liquid dosage forms, the active ingredient is typically either suspended or dissolved in a dispersion medium for delivery. While a tablet or capsule is usually preferred for many reasons (e.g., taste, ease of dosing, ease of manufacturing, shelf stability, etc.), a liquid dosage form may be preferred in certain instances (e.g., a patient's ability to swallow or a desire for extremely rapid dissolution).
To maintain desired therapeutic blood levels for pharmaceutical and/or probiotic active ingredients delivered orally, dosages are commonly taken multiple times a day. This dosing may be bis in die (b.i.d., 2 times a day), ter in die (t.i.d., 3 times a day), quater in die (q.i.d., 4 times a day), or even more frequently. The frequency of dosing needed to maintain therapeutic levels depends on many parameters, including the effective therapeutic blood level range needed for the active ingredient to maintain its effectiveness, as well as the rate at which the body clears the drug (e.g., half-life of the drug).
While maintaining target therapeutic blood levels is one reason for multiple doses of a drug throughout the day, there are other reasons that a single large dose is not preferred as a dosing regimen. Some active ingredients are unstable in areas of the gastrointestinal tract and an extended-release profile can bypass much of the enzymes or other conditions instigating degradation. Furthermore, some active ingredients can irritate the gastrointestinal tract in large doses and a sudden large dose of the drug can be harmful to the patient. In such instances, multiple smaller doses given throughout the day can lessen or eliminate harmful side effects.
No matter the reason for necessitating multiple doses throughout a day, patient compliance with a frequent dosing regimen remains a serious issue. For those medications that require exact dosing, patients must remember to take them at the specified intervals. Outside influences on patients' daily routines, such as alterations in work, sleep, and/or eating times can lead to missed doses. This problem is also evident for younger patients, such as school age children, who may require multiple doses of a prescription medication throughout the school day.
For those active ingredients that require a higher frequency of dosing, the sustained delivery of active ingredients from the dosage form can decrease the frequency of dosing and overall number of doses needed. By reducing the frequency and number of doses, patient compliance can be vastly improved. Additionally, sustained or extended release of active ingredients can lessen the amount of drug delivered all at once, which in turn results in less patient side effects for those drugs that can be harmful at sudden, high doses.
Advances in oral solid dosage forms (e.g., matrix-based tablets and multiparticulates encapsulated into capsules), have enabled the sustained-release delivery of active ingredients via a single dose. These modified release tablets and capsules can deliver the active ingredient via a specific release profile, such as a sustained, extended release—a slow release over a period of many hours. By providing an extended release profile, the dosing frequency requirements may drop significantly, such as from several times a day to only once or twice per day. Furthermore, such sustained release profiles can dramatically limit the fluctuation in blood drug concentrations (i.e., between peak and trough).
Active-containing multiparticulates which are subsequently encapsulated into capsules can be generally considered as having one of two basic forms: beads or granules. Multiparticulate beads are built through distinct manufacturing processes to create round, spherical beads. These spherical beads typically have ingredients other than the active ingredient that help form the bead and maintain its shape. Additionally, beads normally go through a manufacturing process designed to round them and minimize their surface area. Granules meanwhile, are commonly generated using processes that produce irregularly shaped particles. Like beads, granules can be formed using additional excipients which help the granule form and maintain its shape. However, granules can also be prepared containing only active ingredients through certain processes (e.g., dry granulation and crystallization).
There are many ways that oral solid dosage forms can be designed to generate a modified release profile. These include diffusion-based delivery mechanisms (e.g., matrix or reservoir systems), dissolution-based delivery mechanisms (e.g., matrix or encapsulation systems), and osmotic pressure controlled delivery mechanisms. For tablets, all modified release systems can be employed—dissolution-based, diffusion-based, and osmotic pressure controlled. However, for the modified-release of multiparticulates, the reservoir and encapsulation systems make up the vast majority of successful products. These reservoir and encapsulation multiparticulates can display a modified-release profile through a dissolution-based or diffusions-based delivery mechanism, or some combination of the two.
A common example of multiparticulates displaying a combination of dissolution-based and diffusion-based release mechanisms to generate a sustained release profile involves a functional coating applied to an active ingredient core. First a core granule or bead that includes the active ingredient is manufactured. The core bead or granule may then be coated with mostly insoluble material, with a small amount of soluble material incorporated into this coating layer to create pores during release. Drug release occurs after the soluble components of the coating dissolves, creating a pore network which allows entry of the dissolution fluid. The drug transverses from the core to the outer dissolution fluid through the network following a diffusion model. The rate of drug release is dependent on many parameters which can be modified to attenuate the rate of release, including the coating type, coating thickness, type and quantity of soluble pore former in the coating, size of the multiparticulate, surface area of the multiparticulate, and amount of active ingredient in the core, among many others.
One example of sustained release granules is described in U.S. Published Patent Application No. 2003/0104071. This published patent application describes extended release potassium chloride granules consisting essentially of potassium chloride crystals coated only with ethylcellulose for the sustained release of potassium. The granules in this dosage form can be delivered via a hard shell capsule, or formulated into a tablet that disintegrates after ingesting. The extended release of potassium chloride from the granules decreases the need for frequent dosing throughout the day. The extended release also reduces the side effects commonly seen after a patient is administered large doses of potassium chloride, such as gastrointestinal disturbance, weakness, and circulatory disturbances.
Virtually all the pharmaceutical and/or probiotic products that deliver active ingredients orally via an extended release mechanism are solid dosage forms, namely capsules or tablets, with very few exceptions. With these modified release capsule and tablets, patients that normally are required to take a tablet or capsule many times a day may instead take an extended release product once or twice daily. Often, these modified-release capsules and tablets have a higher total amount of active ingredient in them compared to an immediate release dose, with much of the dose spread out over a longer period of release.
However, with the extended release products limited to tablets and capsules, a huge patient population remains insufficiently served—namely those patients who have trouble swallowing solid dosage forms. These patients—whether they are young children, geriatric, physically limited, or incapacitated—must commonly opt for liquid dosage forms, and as such are limited to the immediate release profile that they commonly display.
There are very few examples of sustained-release products on the market designed for a liquid suspension delivery. One example of a sustained-release pharmaceutical product in a liquid suspension form is described in U.S. Pat. No. 6,001,392. The composition generally includes a drug/resin complex that may be carried in a liquid composition wherein the drug is an antitussive. The drug/resin complex utilizes ion-exchange resins, wherein the drug is adsorbed to the resin via ionic bonds to keep the drug in the bead. The release of the drug over time is controlled using additional coating layers to retard the drug release rate. The amount of active ingredient per weight of the bead may be low due to limited adsorption of the drug onto the resin bead, as well as high amounts of additional coating of the bead to facilitate slow release. Additionally, the manufacturing cost of the drug/resin complex is very high, leading to very limited adoption of this technology in the pharmaceutical and/or probiotics industry.